MT1-MMP as a downstream target of BCR-ABL/ABL interactor 1 signaling: polarized distribution and involvement in BCR-ABL-stimulated leukemic cell migration.
MT1-MMP as a downstream target of BCR-ABL/ABL interactor 1 signaling: polarized distribution and involvement in BCR-ABL-stimulated leukemic cell migration.
复制标题
MT1-MMP 作为 BCR-ABL/ABL 相互作用子 1 信号传导的下游靶标：极化分布并参与 BCR-ABL 刺激的白血病细胞迁移。
作者：
Sun,X;Li,Y;Yu,W;Wang,B;Tao,Y;Dai,Z
人类慢性髓性白血病（CML）和急性淋巴细胞白血病（ALL）的一部分是由Bcr-Abl的表达引起的，Bcr-Abl是一种由t (9; 22)（q34; q11）染色体易位产生的融合基因。bcr - abl阳性白血病的特点是骨髓和淋巴系细胞过早释放，随后这些细胞在外周血中扩增，并浸润脾、肝和肺等器官。这些疾病的进展不仅涉及细胞增殖加速和细胞存活增强，而且还涉及细胞运动性增加和白血病细胞通过血管和基质屏障的主动入侵。Bcr-Abl诱导白血病细胞运动增强和侵袭的机制尚不完全清楚。膜型1基质金属蛋白酶（MT1-MMP）是跨膜金属蛋白酶的一员，负责多种细胞外基质（ECM）的降解。1 MT1-MMP也是proMMP2和proMMP13的激活因子，是细胞迁移和侵袭的关键调节因子。1,2在迁移细胞中，MT1-MMP在板足等迁移结构中富集，而在一些肿瘤细胞中，它被发现定位于一种名为invadopodium的特殊迁移/侵袭结构。MT1-MMP的这种极化膜分布被认为是细胞迁移和肿瘤转移的关键。尽管现有证据表明，MT1-MMP与跨膜粘附分子和丝状肌动蛋白（F-actin）的相互作用可能有助于其在肿瘤细胞中的极化分布，但导致这些相互作用的信号通路仍有待阐明。在此之前，我们发现Bcr-Abl在小鼠原b细胞系Ba/F3中的表达诱导了异常的富f -肌动蛋白结构在靠近膜的部位的组装。这种异常结构还富含粘附分子，如b1-整合素。鉴于肌动蛋白细胞骨架和跨膜粘附分子在调节MT1-MMP亚细胞分布中的重要性，我们开始测试bcr - abl诱导的富f -肌动蛋白结构的形成是否影响MT1-MMP的膜分布。此外，由于bcr -Abl诱导的富f -肌动蛋白结构的形成依赖于Abl相互作用因子1 (Abi1)， Abl相互作用因子是肌动蛋白聚合的关键调节因子，我们想知道这一途径是否在bcr -Abl阳性白血病细胞中调节MT1-MMP的膜分布中起作用。
Human chronic myelogenous leukemia (CML) and a subset of acute lymphocytic leukemia (ALL) are caused by expression of Bcr-Abl, a fusion gene generated by reciprocal t (9; 22)(q34; q11) chromosome translocation. Bcr-Abl-positive leukemias are characterized by premature release of myeloid and lymphoid lineage cells from bone marrow, followed by expansion of these cells in peripheral blood and infiltration of organs such as spleen, liver and lung. The progression of these diseases involves not only accelerated cell proliferation and enhanced cell survival, but also increased cell motility and active invasion of leukemic cells through blood vessel and matrix barriers. The mechanism by which Bcr-Abl induces increased motility and invasion of leukemic cells is not completely understood. Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a member of transmembrane metalloproteinases, which is responsible for the degradation of a variety of extracellular matrix (ECM). 1 MT1-MMP is also an activator of proMMP2 as well as proMMP13 and is a key regulator of cell migration and invasion. 1, 2 In migrating cells, MT1-MMP is enriched in migration structures such as lamellipodia, whereas in some tumor cells it is found to localize to a specialized migrating/invasive structure named invadopodium. 3 This polarized membrane distribution of MT1-MMP is believed to be critical for cell migration and tumor metastasis. Although available evidence suggests that the interactions of MT1-MMP with transmembrane adhesion molecules and filamentous actin (F-actin) may contribute to its polarized distribution in tumor cells, 1 the signaling pathways leading to these interactions remain to be elucidated.Previously, we found that the expression of Bcr-Abl in murine pro-B-cell line Ba/F3 induces the assembly of an abnormal F-actin-enriched structure at the sites adjacent to membrane. 4 This abnormal structure is also enriched with adhesion molecules such as b1-integrin. Given the importance of actin cytoskeleton and transmembrane adhesion molecules in regulation of subcellular distribution of MT1-MMP, 1 we set forth to test if Bcr-Abl-induced formation of the F-actin rich structures affects the membrane distribution of MT1-MMP. Furthermore, because Bcr-Abl-induced formation of the F-actin rich structures is dependent on Abl interactor 1 (Abi1), a key regulator of actin polymerization, we asked if this pathway plays a role in regulation of membrane distribution of MT1-MMP in Bcr-Ablpositive leukemic cells.